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FRONTIERS IN IMMUNOLOGY


VACCINES AND MOLECULAR THERAPEUTICS

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THIS ARTICLE IS PART OF THE RESEARCH TOPIC

Immunological Aspects of Vaccine Safety View all 5 Articles

Articles

EDITED BY

MICHAEL VAJDY



EpitoGenesis (United States), United States

REVIEWED BY

SRINIVASA REDDY BONAM



Institut National de la Santé et de la Recherche Médicale (INSERM), France

GREGOR EBERT



Technical University of Munich, Germany

The editor and reviewers' affiliations are the latest provided on their Loop
research profiles and may not reflect their situation at the time of review.

TABLE OF CONTENTS

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   * Results
   * Discussion
   * Summary
   * Data Availability Statement
   * Author Contributions
   * Funding
   * Conflict of Interest
   * Acknowledgments
   * Supplementary Material
   * References




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Open Supplemental Data


HYPOTHESIS AND THEORY ARTICLE

Front. Immunol., 24 February 2021 | https://doi.org/10.3389/fimmu.2021.640093


TWO DIFFERENT ANTIBODY-DEPENDENT ENHANCEMENT (ADE) RISKS FOR SARS-COV-2
ANTIBODIES

Darrell O. Ricke*
 * Biological and Chemical Technologies, Massachusetts Institute of Technology
   Lincoln Laboratory, Biotechnology and Human Systems, Lexington, MA, United
   States

COVID-19 (SARS-CoV-2) disease severity and stages varies from asymptomatic, mild
flu-like symptoms, moderate, severe, critical, and chronic disease. COVID-19
disease progression include lymphopenia, elevated proinflammatory cytokines and
chemokines, accumulation of macrophages and neutrophils in lungs, immune
dysregulation, cytokine storms, acute respiratory distress syndrome (ARDS), etc.
Development of vaccines to severe acute respiratory syndrome (SARS), Middle East
Respiratory Syndrome coronavirus (MERS-CoV), and other coronavirus has been
difficult to create due to vaccine induced enhanced disease responses in animal
models. Multiple betacoronaviruses including SARS-CoV-2 and SARS-CoV-1 expand
cellular tropism by infecting some phagocytic cells (immature macrophages and
dendritic cells) via antibody bound Fc receptor uptake of virus.
Antibody-dependent enhancement (ADE) may be involved in the clinical observation
of increased severity of symptoms associated with early high levels of
SARS-CoV-2 antibodies in patients. Infants with multisystem inflammatory
syndrome in children (MIS-C) associated with COVID-19 may also have ADE caused
by maternally acquired SARS-CoV-2 antibodies bound to mast cells. ADE risks
associated with SARS-CoV-2 has implications for COVID-19 and MIS-C treatments,
B-cell vaccines, SARS-CoV-2 antibody therapy, and convalescent plasma therapy
for patients. SARS-CoV-2 antibodies bound to mast cells may be involved in MIS-C
and multisystem inflammatory syndrome in adults (MIS-A) following initial
COVID-19 infection. SARS-CoV-2 antibodies bound to Fc receptors on macrophages
and mast cells may represent two different mechanisms for ADE in patients. These
two different ADE risks have possible implications for SARS-CoV-2 B-cell
vaccines for subsets of populations based on age, cross-reactive antibodies,
variabilities in antibody levels over time, and pregnancy. These models place
increased emphasis on the importance of developing safe SARS-CoV-2 T cell
vaccines that are not dependent upon antibodies.




INTRODUCTION

The SARS-CoV-2 virus is a unclassified betacoronavirus with sequenced genomes
ranging from 29.8 to 29.9 k RNA bases. The SARS-CoV-2 genome encodes replicase
proteins, structural proteins, and accessory proteins (1). The ORF1a and ORF1ab
polyproteins are proteolytically cleaved into 16 non-structural proteins
designated nsp1-16 (1). Like SARS, COVID-19 manifests as a virulent zoonotic
virus in humans with currently 101,211,750 global cases and 2,183,169 deaths as
of Jan. 28, 2021 (2). The details of SARS-CoV-2 infections and disease
progression are still being worked out. One proposed step in COVID-19 disease
progression involves the nucleocapsid protein binding to the
prostaglandin-endoperoxide synthase 2 (PTGS2)/cyclooxygenase-2 (COX-2) promoter
and upregulating expression resulting in elevated levels of prostaglandin E2
(PGE2) and other inflammatory molecules (3–5). Elevated PGE2 may be driving
hyper-activation of mast cells associated with excess release of histamine and
additional inflammatory molecules (5). COVID-19 is predicted to be a mast cell
disease (6).

Zoonotic MERS-CoV, SARS-CoV-1, and SARS-CoV-2 are evolutionarily related with
similarities in disease progression in humans. The mild variant first phase of
viral progression generally presents with mild flu-like symptoms. For some
individuals, infection progresses to a second moderate-severe variant phase.
Progression to this phase coincidently coincides with timing of anticipated
humoral immunity antibody response from memory B-cells for cross reactive
antibodies. Coronavirus infection of phagocytic cells has been previously
observed. MERS-CoV can infect monocyte-derived macrophages (MDMs),
monocyte-derived dendric cells (MoDCs), and T cells (7, 8). In a mouse animal
model, phagocytic cells contribute to the antibody-mediate elimination of
SARS-CoV-1 (9). This process is expected for patients with mild symptoms who do
not progress to moderate or severe disease. For patients with moderate and
severe symptoms, pathophysiology is consistent with infection of phagocytic
immune cells (immature MDMs and MoDCs). Chemokines attract additional dendritic
cells and immature macrophages that are susceptible to infection leading to a
possible infection amplifying cascade of phagocytic immune cells. For some
patients with severe symptoms, excessive accumulation of macrophages contributes
toward a storm of cytokines (10–12) and chemokines. These viruses also perturb
the adaptive immune responses within infected individuals. Individuals with SARS
have pronounced peripheral T cell lymphocytopenia with reduced CD4+ and CD8+ T
cells (13, 14). MERS-CoV and SARS-CoV are associated with T cell apoptosis (15,
16). Infection of macrophages (17) and some T cells along with viral
dysregulation of cellular pathways result in compromised innate and humoral
immunity in patients in phase II (18). The possibility of migration throughput
the body of infected immune cells and later high virus titer in blood can
account for additional disease pathophysiology clinical observations observed
for these viruses. Other disease differences may simply be the different
population of cells with target host receptors angiotensin I converting enzyme 2
(ACE2) for SARS-CoV-1 and SARS-CoV-2 and dipeptidyl peptidase IV (DPP4) for
MERS-CoV. The increased affinity of the SARS-CoV-2 Spike protein
receptor-binding-domain (RBD) compared to SARS may account for the significant
airborne transmission of SARS-CoV-2 (19). Also, neuropilin-1 facilitates
SARS-CoV-2 cell entry and infectivity (20).

Characterizing variability of viral proteins can inform designing medical
countermeasures (MCMs). For viral progeny, deleterious mutations are selected
against (21). Neutral mutations (22) provide a framework for antigenic drift to
facilitate escape from immune responses; these residues will continue to mutate
over time. The critical-spacer model proposes that proteins have either amino
acid residue side-chains critical for function or have variable side-chains
while possibly function for positioning/folding of critical residues (23). The
divergence model of protein evolution proposes that number of critical residues
for a protein is consistent for evolutionarily closely related proteins (24).
These concepts are applied to SARS-CoV-2 Spike (S) protein leveraging closely
related coronavirus protein sequences to provide insights into viral
vulnerabilities that can be leveraged in designing MCMs. The exposed domain of
the Spike protein exhibits exposed surface areas with high variability.
Increased risk for antibody-dependent enhancement (ADE) from antibodies
targeting SARS-CoV-2, SARS-CoV-1, and MERS-CoV exposed residues is indicated by
observed ADE in animal models and the antibody facilitated infection of
phagocytic immune cells by coronaviruses (9, 25). In addition, SARS-CoV-2
antibodies bound to mast cells may also be involved in ADE for some MIS-C and
MIS-A patients (26).


METHODS

SARS-CoV-2 spike protein sequence from GenBank entry MN908947.3 was searched
against the non-redundant (nr) and PDB database using the NCBI BLASTP web
interface. Hit protein sequences were downloaded. Protein multiple sequence
alignments were created with the Dawn program (27). The Spike structure 6CRZ
(28) was downloaded from RCSB PDB database (29). Dawn variation results were
visualized with the Chimera program (30).


RESULTS

Dawn variation (V <n>) results for SARS-CoV-2 amino acid residues were
classified as 650 V1 residues—dark green, 263 V2 residues—light green, 123 V3
residues—yellow, 107 V4 residues—light blue, and 152 V5+ residues—dark blue
(Figure 1). The dark green residues represent candidate critical residues and
the dark blue residues represent candidate spacer residues (Figure 1). Amino
acid residues with conservative substitutions are also consider critical
residues, and are colored light green in Figure 1; positions with > 95% of a
single residue were included in this category to accommodate potential
sequencing errors and possibly adaptative mutations. The V1+V2 residues
represent 71% of the 1,295 Spike residues. The Spike protein exhibits regions of
extensive variability of exposed surface residues (Figure 1).


FIGURE 1

Figure 1. SARS-CoV-2 Spike protein variation results. Amino acid residue color
code: dark green (critical residues—V1), light green (critical residues with
conservative substitutions or variant in <10 sequences—V2, yellow (three
variants—V3), light blue (four variants—V4; likely spacer residues), and blue
(5+ variants—V5+; spacer residues).





DISCUSSION


VARIATION RESULTS

The observed amino acid variations in SARS-CoV-2 proteins are consistent with
expected natural variations in the context of random mutations and selection in
the context of host immune responses. The Spike protein S1 extended domain shows
the highest number of exposed surface highly variable residues (Figure 1). These
spacer residues may function as exposed antigens for antibody responses with the
possibility of suppressing immune responses to less immunogenic surface
antigens. Many of these Spike protein antigens may lead to non-neutralizing
antibodies. Mutations at these residues may provide antigenic drift to escape
immune responses. As the COVID-19 pandemic continues, Spike mutation variants
are accumulating resulting in the design of vaccine booster shots prior to
initial population vaccinations (31). The Spike protein represents an evolving
vaccine target with parallels to the annual influenza vaccine hemagglutinin and
neuraminidase targets while the COVID-19 pandemic persists enabling rapid virus
evolution in humans.


MULTIPLE CORONAVIRUSES APPROACHES FOR CELL INFECTION

Coronaviruses have multiple approaches for infecting cells by direct receptor
binding and by indirect antibody Fc uptake. The SARS-CoV-2 Spike protein
contains receptor-binding domains (RBD) targeting human angiotensin I converting
enzyme 2 (ACE2) (32, 33); this is the initial route for infecting host cells. To
take advantage of antibody responses, coronaviruses also leverage antibody Fc
uptake to infect some phagocytic immune cells (34). Coronaviruses use the Spike
protein subunit 2 fusion peptide (FP), heptad repeat 1 (HR1), and heptad repeat
2 (HR2) to infect immune cells upon proteolytic cleavage of Spike within
endosomes. HR1 and HR2 form a canonical 6-helix bundle involved in membrane
fusion (35). Jaume et al. (34) found that antibody-mediated infection was
dependent on Fc receptor II and not the endosomal/lysosomal pathway utilized by
ACE2 targeting. Viral infection of complement receptor (CR) cells is an
additional possible route of infecting cells expanding cellular tropism (36).
This expanded cellular tropism mechanism provides coronaviruses like SARS-CoV-1,
MERS-CoV, and SARS-CoV-2 with more than one cellular trophism for infecting host
cells. This leads to the prediction that antibody mediated uptake of virus is
the potential mechanism that induces ADE to cross-reactivity antibodies,
maternally transferred antibodies (matAbs), and vaccines (37–40).


MACROPHAGES AND IMMUNE DYSREGULATION

Macrophages play an important role in disease progression and possibly immune
dysregulation for SARS and COVID-19. Lymphopenia is a common feature in patients
with SARS (13, 41) and COVID-19 (42, 43). Direct infection of subpopulations of
immune cells is possible if they express virus target receptors. Two receptors
have been identified for SARS-CoV-1 including ACE2 (44) and C-type lectin domain
family 4 member M (CLEC4M, CD209L, CD299, DC-SIGN2, DC-SIGNR, HP10347, and
LSIGN) (45) with CLEC4M expressed in human lymph nodes (46). In a mouse model,
depletion of CD4+ T cells resulted in an enhanced immune-mediated interstitial
pneumonitis when challenged with SARS-CoV-1 (47). But, depletion of CD4+ and
CD8+ T cells and antibodies enabled the innate defense mechanisms to control the
SARS-CoV-1 virus without immune dysregulation (47). Similar results were also
observed in mice with SARS-CoV-1 challenge, but treatment with liposomes
containing clodronate, which deplete alveolar macrophages (AM), prevented immune
deficient virus-specific T cell response (48). These studies point to an
interplay between antibodies and macrophages in ADE responses in animal models.
In a macaque model, anti-spike IgG causes acute lung injury by skewing
macrophage response toward proinflammatory monocyte/macrophage recruitment and
accumulation during acute SARS-CoV-1 infection (49). Blockade of in vitro human
activated macrophages FcγR reduced proinflammatory cytokine production (49).
CD169+ macrophages have ACE2 and are susceptible to SARS-CoV-2 infection (50).
Both M1- and M2-type macrophages are susceptible to SARS-CoV-2 infection (51).
These observations are likely linked by antibody-dependent enhancement of
coronavirus infection of macrophages (34, 52). The pathophysiology of moderate
and severe SARS and COVID-19 diseases fits a proposed model of
antibody-dependent infection of macrophages as the key gate step in disease
progression from mild to moderate and severe symptoms contributing to
dysregulated immune responses (53) including apoptosis for some T cells/T cell
lymphopenia, proinflammatory cascade with macrophage accumulation, and cytokine
and chemokine accumulations in lungs with a cytokine storm in some patients.
Infected phagocytic immune cells may enable the virus to spread to additional
organs prior to viral sepsis (Figure 2).


FIGURE 2

Figure 2. Disease progression model with normal immune responses during the
initial mild symptoms phase (see 1–3). Antigen presenting cells migrate to the
lymph nodes to activate T cells (2a). The progression gate to moderate and
server disease is the infection of phagocytic immune cells (3a) leading to
immune dysregulation (4b). In the lungs, chemokines attract additional dendritic
cells and immature macrophages that are subsequently infected in an positive
feedback-loop infection cascade (4b). Infected phagocytic immune cells
disseminate throughout the body infecting additional organs (5 & 6). Levels of
chemokine and cytokines in the lungs from infected cells can create a cytokine
storm (6).





ANTIBODY-DEPENDENT ENHANCEMENT (ADE) OF CORONAVIRUSES

Antibody-dependent enhancement (ADE) may develop via more than one molecular
mechanism. One model suggestions that antibody/Fc-receptor complex functionally
mimics viral receptor enabling expanded host cell trophism of some phagocytic
cells (54). Wan et al. (54) illustrate an antibody dosage effect for enhancing
disease or inhibiting the virus dependent upon the antibody dosage. It is
well-established that antibodies to one strain of a virus may be subneutralizing
or non-neutralizing for viral infections of different strains (55–57). Infection
of cells expressing Fc-gamma was shown for SARS-CoV-1 (58). A possible case of
ADE was observed in a patient with a second SARS-CoV-2 infection (59). Early
vaccine results show significant antibody responses by day 14 (60) which
represents memory B-cell responses (i.e., original antigenic sin) with
cross-reactivity antibodies from likely other coronavirus strain(s). Early high
antibody responses are correlated with increased disease severity for both SARS
(61) and COVID-19 (62–67). Wu et al. demonstrated that antibodies from COVID-19
patients enabled SARS-CoV-2 infections of Raji cells (lymphoma cells derived
from B lymphocytes), K562 cells (derived from monocytes), and primary B cells
(68). SARS-CoV-2 infection of some phagocytic cells (i.e., macrophages) may be a
key gate step in disease progression for some patients.


MAST CELLS RISKS FOR ADE AND MULTISYSTEM INFLAMMATORY SYNDROMES (MIS-C & MIS-A)

Mast cells can degranulated by both IgE and IgG antibodies bound to Fc receptors
(69). Cardiac injury is a common condition among hospitalized COVID-19 patients
and is associated with higher risk of mortality (70). However, pathological
manifestations of heart tissues found only scarce interstitial mononuclear
inflammatory infiltrates without substantial myocardial damage (42). Myocardial
injury significantly correlates with fatal outcome for COVID-19 (71).
Multisystem inflammatory syndrome in children (MIS-C) and adults (MIS-A)
associated with COVID-19 has appeared in areas following SARS-CoV-2 outbreaks. A
model of MIS-C has been proposed where activation and degranulation of mast
cells with Fc receptor-bound SARS-CoV-2 antibodies leads to increased histamine
levels (26). This model is consistent with MIS-C in infants with maternally
transferred antibodies (matAbs) (37–40) to SARS-CoV-2. SARS-CoV-2 nucleocapsid
binding to PTGS2 prompter resulting in upregulated prostaglandin E2 (PGE2) in
COVID-19 patients (4). Elevated PGE2 may be driving hyper-activated mast cells
as an alternative mechanism driving increased histamine levels in older children
and adults. These increased histamine levels are predicted to impede blood flow
through cardiac capillaries due to constricted pericytes with increased risk for
cardiac pathology due to cell death by anoxia and coronary artery aneurysms due
to increased blood pressure (26). An instance of a 12 years old child with a
previous asymptomatic COVID-19 infection developing MIS-C on likely second
infection has been reported (72).


VACCINE RISKS FOR ANTIBODY-DEPENDENT ENHANCEMENT (ADE)

Virus vaccines can use live-attenuated virus strains, inactivated (killed)
virus, protein subunit, messenger ribonucleic acid (mRNA), or deoxyribonucleic
acid (DNA) vaccine. Antibodies induced by vaccines can be neutralizing or
non-neutralizing. Non-neutralizing antibodies can contribute to anti-viral
activities with mechanisms including antibody-medicated complement-dependent
cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC),
antibody-dependent cellular phagocytosis (ADCP) [reviewed (73)]. The yearly
influenza vaccine induces both neutralizing and non-neutralizing antibodies that
provide projection against the strains in the vaccine and closely related
strains. Vaccine-associated enhanced disease (VAED) can result when there are
multiple circularizing serotypes of virus [e.g., Dengue fever (55–57)] or when
the virus uses antibodies for expanded host cell trophism of phagocytic immune
cells.

Many of the viruses associated with ADE have cell membrane fusion mechanisms
(38). For influenza A H1N1, vaccine-induced cross-reactive anti-HA2 antibodies
in a swine model promote virus fusion causing vaccine-associated enhanced
respiratory disease (VAERD) (74). ADE was observed for the respiratory syncytial
virus (RSV) in the Bonnet monkey model (37). Van Erp et al. (37) recommends
avoidance of induction of respiratory syncytial virus (RSV) non-neutralizing
antibodies or subneutralizing antibodies to avoid ADE. ADE has been observed in
multiple SARS-CoV-1 animal models. In a mouse model, attempts to create vaccines
for SARS-CoV-1 lead to pulmonary immunopathology upon challenge with SARS-CoV-1
(75, 76); these vaccines included inactivated whole viruses, inactivated viruses
with adjuvant, and a recombinant DNA spike (S) protein vaccine in a virus-like
particle (VLP) vaccine. Severe pneumonia was observed in mice vaccinated with
nucleocapsid protein after challenge with SARS-CoV-1 (77). Enhanced hepatitis
was observed in a ferret model with a vaccine with recombinant modified vaccinia
virus Ankara (rMVA) expressing the SARS-CoV-1 Spike protein (78). ADE was
observed for rhesus macaques with SARS-CoV-1 vaccine (79). SARS-CoV-1 ADE is
mediated by spike protein antibodies (80). Antibodies to the SARS-CoV-1 spike
protein can mediate viral entry via Fc receptor-expressing cells in a
dose-dependent manner (54). Jaume et al. (34) point out the potential pitfalls
associated with immunizations against SARS-CoV-1 Spike protein due to Fc mediate
infection of immune cells. This leads to the prediction that new attempts to
create either SARS-CoV-1 vaccines, MERS-CoV vaccines (81), or SARS-CoV-2
vaccines have potentially higher risks for inducing ADE in humans facilitated by
antibody infection of phagocytic immune cells. This potential ADE risk is
independent of the vaccine technology (82) or targeting strategy selected due to
predicted phagocytic immune cell infections upon antibody uptake. For MERS
patients, the seroconversion rate increased with disease severity (83). Severe
clinical worsening for SARS patients occurs concurrently with timing of IgG
seroconversion (84). Clinical evidence of early high IgG responses in SARS
patients is correlated with disease progression (85) and severity (62–67).
Antibody treatments for critically ill COVID-19 patients have been halted due to
a potential safety signal and unfavorable risk-benefit profile (86). Current
SARS-CoV-2 vaccines appear to be providing protection with high antibody titers;
the possibility of ADE risks associated with waning titers of antibodies over
time remains unknown.


CONVALESCENT PLASMA THERAPY

Convalescent plasma therapy takes the antibodies from a recovering patient and
provides them to patients with active infections. COVID-19 results for
convalescent plasma therapy appear to have mixed results with no statistically
significant improvement in randomized clinical trials (87, 88): in a trial, no
significant difference in 28-days mortality (15.7 vs 24.0% odds ratio: 0.59, p =
0.30) was observed in a randomized trial (87); and, in the PLACID trial,
progression to severe disease or all-cause mortality at 28 days occurred in 44
(19%) convalescent plasma arm vs. 41 (18%) control arm (risk ratio 1.04) (88).
Neither trial mentions antibody-dependent enhancement in context of progression
to severe disease or all-cause mortality. For SARS, a higher discharge rate was
observed amount patients who were given convalescent plasma before day 14 of
illness (58.3%) vs. after 14 days (15.6%), p < 0.001; the mortality rate for the
second group was 21.9% which was higher than the all SARS-related mortality rate
in Hong Kong of 17% (89); while this looks promising for most patients, the
increased mortality above the regional average observed for patients after 14
days of illness should be noted.


ANTIBODY TARGETS

Analyzing the Cryo-EM structures of MERS-CoV and SARS-CoV-1 spike (S)
glycoproteins, Yuan et al. (90) suggest that the fusion peptide (FP) and the
heptad repeat 1 region (HR1) are potential targets for eliciting broadly
neutralizing antibodies based on exposure on the surface of the stem region,
with no N-linked glycosylation sites in this region, and sequence conservation.
Antibodies that interrupt virus-cell fusion will likely block the infection of
immune cells using Fc-mediated uptake of virus (34). This has been demonstrated
for SARS-CoV-1 for antibodies to the HR2 region (91–93). Likewise, SARS-CoV-2
antibodies that block cell fusion are likely to not share the same ADE risk of
other SARS-CoV-2 antibodies.


B CELL VACCINE DESIGNS

B cell vaccines that target the Spike protein cell fusion mechanisms have the
highest chance of raising neutralizing antibodies with minimal or no ADE risk
due to antibody binding sterically blocking cell fusion. Antibodies targeting
other portions of the Spike protein or other SARS-CoV-2 exposed proteins may
enable infection of phagocytic immune cells even if they are neutralizing.


T CELL VACCINE DESIGNS

T cell vaccines that target SARS-CoV-2 replicase proteins have the highest
change of avoiding viral escape by antigenic variation and accumulation of
mutations in variable residues. Lisziewicz and Lori (94) described an approach
for developing a T cell COVID-19 vaccine. EpiVax EPV-CoV19 (95) is an example
COVID-19 T cell vaccine.


SUMMARY

Given past data on multiple SARS-CoV-1 and MERS-CoV vaccine efforts have failed
due to ADE in animal models (75, 81), it is reasonable to hypothesize a similar
ADE risk for SARS-CoV-2 antibodies and vaccines. ADE risks may be associated
with antibody level (which can wane over time after vaccination) and also if the
antibodies are derived from prior exposures to other coronaviruses. In addition,
ADE with mast cells likely plays a role in MIS-C for infants and possibly older
MIS-C and MIS-A patients. While expanded trophism of SARS-CoV-2 represents a
possible ADE risk in the subset of COVID-19 patients with disease progression
beyond the mild disease stage.


DATA AVAILABILITY STATEMENT

The datasets presented in this study can be found in online repositories. The
names of the repository/repositories and accession number(s) can be found in the
article/Supplementary Material.


AUTHOR CONTRIBUTIONS

DR conceived of the presented ideas, analyzed the data, and wrote the
manuscript.


FUNDING

This material is based upon work supported by the Under Secretary of Defense for
Research and Engineering under Air Force Contract No. FA8702-15-D-0001. Any
opinions, findings, conclusions or recommendations expressed in this material
are those of the author(s) and do not necessarily reflect the views of the Under
Secretary of Defense for Research and Engineering.


CONFLICT OF INTEREST

The author declares that the research was conducted in the absence of any
commercial or financial relationships that could be construed as a potential
conflict of interest.


ACKNOWLEDGMENTS

We acknowledges the Department of Defense(DoD), Defense Threat Reduction
Agency(DTRA), and The Joint Science and Technology Office(JSTO) of the Chemical
and Biological Defense Program (CBDP) for their support under the Discovery of
Medical countermeasures Against Novel Entities (DOMANE) initiative. We
acknowledges Nora Smith for literature search assistance and Irene Stapleford
for graphic art assistance.


SUPPLEMENTARY MATERIAL

The Supplementary Material for this article can be found online at:
https://www.frontiersin.org/articles/10.3389/fimmu.2021.640093/full#supplementary-material


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Keywords: antibody dependent enhancement, ADE, COVID-19, SARS-CoV-2, multisystem
inflammatory syndrome, MIS-C, antibody dependent enhancement

Citation: Ricke DO (2021) Two Different Antibody-Dependent Enhancement (ADE)
Risks for SARS-CoV-2 Antibodies. Front. Immunol. 12:640093. doi:
10.3389/fimmu.2021.640093

Received: 10 December 2020; Accepted: 03 February 2021;
Published: 24 February 2021.

Edited by:

Michael Vajdy, EpitoGenesis, United States

Reviewed by:

Gregor Ebert, Walter and Eliza Hall Institute of Medical Research, Australia
Srinivasa Reddy Bonam, Institut National de la Santé et de la Recherche Médicale
(INSERM), France

Copyright © 2021 Ricke. This is an open-access article distributed under the
terms of the Creative Commons Attribution License (CC BY). The use, distribution
or reproduction in other forums is permitted, provided the original author(s)
and the copyright owner(s) are credited and that the original publication in
this journal is cited, in accordance with accepted academic practice. No use,
distribution or reproduction is permitted which does not comply with these
terms.

*Correspondence: Darrell O. Ricke, darrell.ricke@ll.mit.edu



Disclaimer: All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated organizations, or
those of the publisher, the editors and the reviewers. Any product that may be
evaluated in this article or claim that may be made by its manufacturer is not
guaranteed or endorsed by the publisher.



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